Transmucosal delivery has many advantages as a method for the administration of beneficial agents. Because of the potential to achieve both a systemic and localized effect, e.g., a systemic and local immune response, transmucosal administration is attractive for its ability to be tailored to the needs of a particular beneficial regimen. The rapid onset of therapeutic action can be advantageous, and mucociliary activity results in faster clearance of medication, thus increasing the bioavailability of the beneficial agent. Compared with other routes, administration of large molecules such as proteins and peptides is rapid and efficient. Transmucosal delivery involves relatively simple, low cost methods of application such as aerosols and liquids that can be delivered via nebulizers, bottles, applicators and syringes. Ease of administration often results in improved patient compliance as compared with intravenous delivery.
Many types of active agents have been evaluated as candidates for transmucosal administration. The mucous membrane of the nasal cavity is frequently used for the delivery of anti-allergens as well as medications useful in the treatment of localized infections. More recently, the nasal route has been exploited for the delivery of anti-migraine drugs, peptides useful in the treatment of osteoporosis, diabetes, prostate cancer, and vaccines.
The mucous membranes are an ideal location for the introduction of vaccines. Successful use of a vaccine, which may consist of preparations of weakened or dead pathogens, requires an immune system response in order to elicit protection against infection. Because they are the primary site of many pathogen-host encounters, mucous membranes are characterized by a strong immune system response to foreign material. In addition, the mucous membrane often represents a relatively hospitable environment for pathogens and antigens alike.
Many prophylactic and treatment regimes require numerous intramuscular (IM) or subcutaneous (SC) injections of antigens. As an example, currently there are two commercially available anthrax vaccines and five recombinant subunit PA (Protective Antigen) vaccines in development. A vaccine licensed for human use in the United Kingdom contains PA from Bacillus anthracis filtrate precipitated with alum; it requires four IM doses in a six-month period. A vaccine licensed for use in humans in the United States is Anthrax Vaccine Adsorbed (AVA), which employs aluminum-hydroxide adsorbed PA from the culture supernatant of a specific B. anthracis strain. AVA requires six subcutaneous doses in 18 months (at 0, 2, and 4 weeks and 6, 12, and 18 months) and subsequent yearly boosters. It gives reasonable protection against inhalation anthrax but is reputed to cause adverse effects in some individuals. AVA contains 50 μg protein per dose, as well as aluminum hydroxide (0.65 mg aluminum/dose) as adjuvant, benzethonium chloride (0.0025%) as a preservative, and formaldehyde (0.01%) as stabilizer. Both of these commercially available vaccines can cause local reactions.
Chitosan, a derivative of the natural polymer chitin, has been investigated as a bioadhesive material and as an adjuvant in transmucosal delivery systems. Unfortunately, the use of effective amounts of chitosan can result in highly viscous formulations. Furthermore, chitosan is insoluble in aqueous solutions with a pH above 6.5. Since the pH in the nasal mucosa is approximately 7, formulations containing chitosan may lose potency when applied to the nasal mucosa.
Accordingly, there remains a need in the art for improved formulations, systems, and methods for transmucosal administration of beneficial agents. Ideally, a transmucosal delivery system would (1) provide for sustained release of any of a variety of beneficial agents, (2) be capable of placement on and delivery across different mucosal surfaces of the body, (3) allow control over the length of the time period during which active agent delivery takes place, and (4) provide rapid onset of action and increased bioavailability. An optimal transmucosal delivery system for administration of vaccines should also provide for an enhanced immune response and an increase in efficacy.